急性髓系白血病患者hDMP1基因表达的变化
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摘要
目的：探讨急性髓系白血病(AML)中hDMP1基因表达特点及其临床意义，并分析其与WT1基因表达水平、NPM1和FLT_3-ITD基因突变的关系。
方法：应用实时定量RT-PCR方法检测93例初诊AML患者骨髓细胞hDMP1和WT1基因的表达水平，以β胆色原脱氢酶(GAPDH)表达水平为内参。同时采用DNA测序分析检测NPM1及FLT_3-ITD突变。分析hDMP1基因表达水平与患者临床资料、WT1基因表达水平、NPM1突变和FLT_3-ITD突变关系。
结果：93例AML患者骨髓细胞中hDMP1基因中位表达水平476.6(60～2217)较对照组2103（470～3770）显著降低(P=0.002)，WT1基因表达水平202.6(49-1134)较正常对照组1.22（0～8.56）显著升高(P=0.001)，hDMP1和WT1基因表达水平与患者性别、年龄、有无肝脾淋巴结肿大、起病时外周血WBC计数、骨髓中原始细胞比例、AML亚型、染色体核型分组无关。36例正常核型AML中，8例检测到NPM1阳性突变（22.22%），7例检出FLT_3-ITD突变阳性患者(19.44%)；22例异常核型AML中未检出NPM1基因突变，2例检出FLT_3-ITD突变阳性(5.56%)。NMP1突变组和非突变组hDMP1基因（p=0.15）和WT1基因（p=0.715）表达水平无统计学差异；FLT3-ITD突变组和非突变组hDMP1基因（p=0.692）和WT1基因（p=0.539）表达水平也无统计学差异。
结论：急性髓系白血病患者hDMP1基因的低表达伴随WT1基因高表达，两者均参与AML发病。hDMP1基因表达水平与NPM1基因突变和FLT_3-ITD突变无关。
Objective To investigate the clinical significance of hDMP1gene expression levelsin acute myeloid leukemias (AMLs) and the correlation between hDMP1and WT1geneexpression, NPM1and FLT_3-ITD gene mutations.
Method Real-time quantitative reverse transcriptase polymerase chain reaction(RT-PCR) was applied to detect the hDMP1and WT1gene expression levels in the bonemarrow cells of93newly diagnosed AMLs and13Healthy volunteers, taking GAPDH ashousekeeping gene. DNA sequencing analysis was used to detect NPM1and FLT3-ITDmutation of the same sample simultaneously. The relationship between hDMP1geneexpression level and clinical features, the WT1gene expression level, NPM1mutationsand FLT_3-ITD mutation were further analysed.
Results The hDMP1gene expression levels in AML patients were significantly lowerthan those in normal controls (P=0.002), while WT1gene expression reversely higherin AMLs than in normal controls (P=0.001). Furthermore both hDMP1and WT1geneexpression levels were of no relevance to sex, age, hepatosplenomegaly, white bloodcell(WBC) count of peripheral blood, the proportion of blasts in bone marrow cells, theFAB subtype of AML or karyotype. Of the36AML cases with normal karyotype, eightwere NPM1mutation-positive (22.22%) and seven cases were FLT_3-ITD mutation-positive(19.44%). Of the22AML cases with abnormal karyotype, two were FLT3-ITDmutation-positive (5.56%) and no NPM1gene mutation was detected. Both hDMP1gene(p=0.15) and WT1gene (p=0.715) expression levels was of no significant differencebetween NMP1mutation group and non-mutation group; nor between FLT_3-ITD mutationgroup and non-mutation group (p=0.692, p=0.539).
Conclusion hDMP1gene was hypo-expressed in AMLs, while WT1geneover-expressed, indicating both the two genes might participate in the pathogenesis ofacute myeloid leukemia. hDMP1gene expression level were of no relationship with NPM1or FLT_3-ITD gene mutation.
方法：应用实时定量RT-PCR方法检测93例初诊AML患者骨髓细胞hDMP1和WT1基因的表达水平，以β胆色原脱氢酶(GAPDH)表达水平为内参。同时采用DNA测序分析检测NPM1及FLT_3-ITD突变。分析hDMP1基因表达水平与患者临床资料、WT1基因表达水平、NPM1突变和FLT_3-ITD突变关系。
结果：93例AML患者骨髓细胞中hDMP1基因中位表达水平476.6(60～2217)较对照组2103（470～3770）显著降低(P=0.002)，WT1基因表达水平202.6(49-1134)较正常对照组1.22（0～8.56）显著升高(P=0.001)，hDMP1和WT1基因表达水平与患者性别、年龄、有无肝脾淋巴结肿大、起病时外周血WBC计数、骨髓中原始细胞比例、AML亚型、染色体核型分组无关。36例正常核型AML中，8例检测到NPM1阳性突变（22.22%），7例检出FLT_3-ITD突变阳性患者(19.44%)；22例异常核型AML中未检出NPM1基因突变，2例检出FLT_3-ITD突变阳性(5.56%)。NMP1突变组和非突变组hDMP1基因（p=0.15）和WT1基因（p=0.715）表达水平无统计学差异；FLT3-ITD突变组和非突变组hDMP1基因（p=0.692）和WT1基因（p=0.539）表达水平也无统计学差异。
结论：急性髓系白血病患者hDMP1基因的低表达伴随WT1基因高表达，两者均参与AML发病。hDMP1基因表达水平与NPM1基因突变和FLT_3-ITD突变无关。
Objective To investigate the clinical significance of hDMP1gene expression levelsin acute myeloid leukemias (AMLs) and the correlation between hDMP1and WT1geneexpression, NPM1and FLT_3-ITD gene mutations.
Method Real-time quantitative reverse transcriptase polymerase chain reaction(RT-PCR) was applied to detect the hDMP1and WT1gene expression levels in the bonemarrow cells of93newly diagnosed AMLs and13Healthy volunteers, taking GAPDH ashousekeeping gene. DNA sequencing analysis was used to detect NPM1and FLT3-ITDmutation of the same sample simultaneously. The relationship between hDMP1geneexpression level and clinical features, the WT1gene expression level, NPM1mutationsand FLT_3-ITD mutation were further analysed.
Results The hDMP1gene expression levels in AML patients were significantly lowerthan those in normal controls (P=0.002), while WT1gene expression reversely higherin AMLs than in normal controls (P=0.001). Furthermore both hDMP1and WT1geneexpression levels were of no relevance to sex, age, hepatosplenomegaly, white bloodcell(WBC) count of peripheral blood, the proportion of blasts in bone marrow cells, theFAB subtype of AML or karyotype. Of the36AML cases with normal karyotype, eightwere NPM1mutation-positive (22.22%) and seven cases were FLT_3-ITD mutation-positive(19.44%). Of the22AML cases with abnormal karyotype, two were FLT3-ITDmutation-positive (5.56%) and no NPM1gene mutation was detected. Both hDMP1gene(p=0.15) and WT1gene (p=0.715) expression levels was of no significant differencebetween NMP1mutation group and non-mutation group; nor between FLT_3-ITD mutationgroup and non-mutation group (p=0.692, p=0.539).
Conclusion hDMP1gene was hypo-expressed in AMLs, while WT1geneover-expressed, indicating both the two genes might participate in the pathogenesis ofacute myeloid leukemia. hDMP1gene expression level were of no relationship with NPM1or FLT_3-ITD gene mutation.
引文
[1] Inoue K, Mallakin A, Frazier DP. Dmp1and tumor suppression. Oncogene.2007;26:4329-4335.
[2] Sugiyama T, Frazier DP, Taneja P, et al. Signal transduction involving the dmp1transcription factor and its alteration in human cancer. Clin Med Oncol.2008;2:209-219.
[3] Hou HA, Huang TC, Lin LI, et al. WT1mutation in470adult patients with acutemyeloid leukemia: stability during disease evolution and implication of itsincorporation into a survival scoring system. Blood.2010;115:5222-5231.
[4]顾伟英,陈子兴,胡绍燕,等. WT1基因水平动态检测对白血病患者异基因骨髓移植后微小残留病监测的意义.中华医学杂志.2005;85:444-447.
[5]顾伟英,曹祥山,邱国强,等. WT1基因肽诱导细胞毒性T淋巴细胞免疫治疗白血病的实验研究.中华医学杂志.2005;85:3475-3480.
[6]顾伟英,陈子兴,邱国强,等.肾母细胞瘤基因衍生肽诱导细胞毒性t淋巴细胞对白血病患者骨髓CD34+细胞的体外杀伤效应.中华医学杂志.2008;88:3401-3406.
[7] Algar E. A review of the Wilms' tumor1gene (WT1) and its role in hematopoiesisand leukemia. J Hematother Stem Cell Res.2002;11:589-599.
[8] Tschan MP, Gullberg U, Shan D, et al. The hDMP1tumor suppressor is a new WT1target in myeloid leukemias. Leukemia.2008;22:1087-1090.
[9]江庭秀,顾伟英,邱国强,等.辛伐他汀联合全反式维甲酸对人早幼粒细胞白血病细胞株WT1/hDMP1基因表达的影响.中华医学杂志.2011;91:1856-1860.
[10] Elmaagacli AH, Koldehoff M, Peceny R, et al. WT1and BCR-ABL specific smallinterfering RNA have additive effects in the induction of apoptosis in leukemiccells. Haematologica.2005;90:326-334.
[11] Rizzi M, Tschan MP, Britschgi C, et al. The death-associated protein kinase2isup-regulated during normal myeloid differentiation and enhances neutrophilmaturation in myeloid leukemic cells. J Leukoc Biol.2007;81:1599-1608.
[12] Svedberg H, Chylicki K, Baldetorp B, et al. Constitutive expression of the Wilms'tumor gene (WT1) in the leukemic cell line U937blocks parts of the differentiationprogram. Oncogene.1998;16:925-932.
[13] Falini B, Mecucci C, Tiacci E, et al. Cytoplasmic nucleophosmin in acutemyelogenous leukemia with a normal karyotype. N Engl J Med.2005;352:254-266.
[14] Yan LZ, Chen SN, Liang JY, et al.[Analysis of NPM1gene mutations in acutemyeloid leukemia]. Zhonghua Xue Ye Xue Za Zhi.2007;28:289-293.
[15] Cloos J, Goemans BF, Hess CJ, et al. Stability and prognostic influence of FLT3mutations in paired initial and relapsed AML samples. Leukemia.2006;20:1217-1220.
[16] Gu W, Chen Z, Hu S, et al. Changes in expression of WT1isoforms during induceddifferentiation of the NB4cell line. Haematologica.2005;90:403-405.
[1]江庭秀,顾伟英,邱国强等.辛伐他汀联合全反式维甲酸对人早幼粒细胞白血病细胞株WT1/hDMP1基因表达的影响.中华医学杂志.2011;91:1856-1860..
[2]顾伟英,陈子兴,胡绍燕等.WT1基因水平动态检测对白血病患者异基因骨髓移植后微小残留病监测的意义.中华医学杂志.2005;85:444-447..
[3] Quentmeier H，Martelli MP，Dirks WG，et a1．Cell line OCI／AML3bearsexon-12NPM gene mutation-A and cytoplasmic expression ofnucleophosmin．Leukemia，2005，19：1760—1767．
[4]王莉红，周春林，张新伟等. FLT3基因内部串联重复突变与急性白血病的关系及临床意义.中华血液学杂志,2004,25:393-396.
[5] Grimwade D, Walker H, Harrison G, et al. The predictive value of hierarchicalcytogenetic classification in older adults with acute myeloid leukemia (AML):analysis of1065patients entered into the United Kingdom Medical ResearchCouncil AML11trial. Blood.2001;98:1312-1320.
[6] Sugiyama T, Frazier DP, Taneja P, et al. Signal transduction involving the dmp1transcription factor and its alteration in human cancer. Clin Med Oncol.2008;2:209-219.
[7] Tschan MP, Gullberg U, Shan D, et al. The hDMP1tumor suppressor is a new WT1target in myeloid leukemias. Leukemia.2008;22:1087-1090.
[8] Tschan MP, Fischer KM, Fung VS, et al. Alternative splicing of the human cyclinD-binding Myb-like protein (hDMP1) yields a truncated protein isoform that altersmacrophage differentiation patterns. J Biol Chem.2003;278:42750-42760.
[9] Elmaagacli AH, Koldehoff M, Peceny R, et al. WT1and BCR-ABL specific smallinterfering RNA have additive effects in the induction of apoptosis in leukemiccells. Haematologica.2005;90:326-334.
[10] Inoue K, Mallakin A, Frazier DP. Dmp1and tumor suppression. Oncogene.2007;26:4329-4335.
[11] Santamaria CM, Chillon MC, Garcia-Sanz R, et al. Molecular stratification modelfor prognosis in cytogenetically normal acute myeloid leukemia. Blood.2009;114:148-152.
[12] Ho PA, Zeng R, Alonzo TA, et al. Prevalence and prognostic implications of WT1mutations in pediatric acute myeloid leukemia (AML): a report from the Children'sOncology Group. Blood.2010;116:702-710.
[13] Suzuki T, Kiyoi H, Ozeki K, et al. Clinical characteristics and prognosticimplications of NPM1mutations in acute myeloid leukemia. Blood.2005;106:2854-2861.
[14] Falini B, Mecucci C, Tiacci E, et al. Cytoplasmic nucleophosmin in acutemyelogenous leukemia with a normal karyotype. N Engl J Med.2005;352:254-266.
[15] Thiede C, Koch S, Creutzig E, et al. Prevalence and prognostic impact of NPM1mutations in1485adult patients with acute myeloid leukemia (AML). Blood.2006;107:4011-4020.
[16] Chen W, Rassidakis GZ, Li J, et al. High frequency of NPM1gene mutations in acutemyeloid leukemia with prominent nuclear invaginations ("cuplike" nuclei). Blood.2006;108:1783-1784.
[17] Schneider F, Hoster E, Schneider S, et al. Age-dependent frequencies of NPM1mutations and FLT3-ITD in patients with normal karyotype AML (NK-AML). AnnHematol.2012;91:9-18.
[18] Kim HJ. Mutations in AML with a normal karyotype: NPM1and FLT3-ITD, ready touse as a key prognosticator? Korean J Hematol.2010;45:79-80.
[19] Hou HA, Huang TC, Lin LI, et al. WT1mutation in470adult patients with acutemyeloid leukemia: stability during disease evolution and implication of itsincorporation into a survival scoring system. Blood.2010;115:5222-5231.
[20]顾伟英,曹祥山,邱国强等. WT1基因肽诱导细胞毒性T淋巴细胞免疫治疗白血病的实验研究.中华医学杂志.2005;85:3475-3480.
[21]顾伟英,陈子兴,邱国强等.肾母细胞瘤基因衍生肽诱导细胞毒性T淋巴细胞对白血病患者骨髓CD34+细胞的体外杀伤效应.中华医学杂志.2008;88:3401-3406.
[1] Sherr CJ.(2000). The Pezcoller lecture: cancer cell cycle revisited. Cancer Res60:3689–3695.
[2] Sherr CJ, Robers JM.(2004). Living with or without cyclin and cyclin-dependentkinases. Genes Dev18:2699–2711.
[3] Giacinti C, Giordano A.(2006).RB and cell cycle progression. Oncogene25:5220–5227.
[4] Evers R, Grummt I.(1995). Molecular coevolution of mammalian ribosomal geneterminator sequences and the transcription termination factor TTF-1. Proc Natl AcadSci USA92:5827–5831.
[5] Inoue K, Sherr CJ.(1998). Gene expression and cell cycle arrest mediated bytranscription factor DMP1is antagonized by D-type cyclins through acyclin-dependent-kinase independent mechanism. Mol Cell Biol18:1590–1600.
[6] Hirai H, Sherr CJ.(1996). Interaction of D-type cyclins with a novel myb-liketranscription factor, DMP1. Mol Cell Biol16:6457–6467.
[7] Cheng M, Sexl V, Sherr CJ, Roussel MF.(1998). Assembly of cyclin D-dependentkinase and titration of p27kip1regulated by mitogen-activated protein kinase kinase(MEK1). Proc Natl Acad Sci USA95:1091–1096.
[8] Oh I-H, Reddy EP.(1999). The myb gene family in cell growth, differentiation, andapoptosis. Oncogene18:3017–3033.
[9] Bernards R.(1999). CDK-independent activities of D type cyclins. Biochem BiophysActa1424(2–3):M17–M22.
[10] Zwijsen R, Wientjens E, Klompmaker R, van der Sman J, Bernards R, Michalides R.(1997). CDK-independent activation of estrogen receptor by cyclin D1. Cell88:405–415.
[11] Adnane, J., Shao, Z. and Robbins, P.D.1999. Cyclin D1associates with theTBP-associated factor TAF(II)250to regulate Sp1-mediated transcription.Oncogene,18:239–47.
[12] Reutens, A.T., Fu, M., Wang, C., Albanese, C., McPhaul, M.J., Sun, Z., Balk, S.P.,Janne, O.A., Palvimo, J.J. and Pestell, R.G.2001. Cyclin D1binds the androgenreceptor and regulates hormone-dependent signaling in a p300/CBP-associated factor(P/CAF)-dependent manner. Mol. Endocrinol.,15:797–811.
[13] Ganter B, Fu S, Lipsick JS.(1998). D-type cyclins repress transcriptional activationby the v-Myb but not the c-Myb DNA-binding domain. EMBO J17:255–268.
[14] Horstmann S, Ferrari S, Klempnauer KH.(2000). Regulation of B-Myb activity bycyclin D1. Oncogene19:298–306.
[15] Landis MW, Pawlyk BS, Li T, Sicinski P, Hinds PW.(2006). Cyclin D1-dependentkinase activity in murine development and mammary tumorigenesis. Cancer Cell9:13–22.
[16] Kim WY, Sharpless NE.(2006). The regulation of INK4/ARF in cancer and aging.Cell127:265–275.
[17] Inoue K, Roussel MF, Sherr CJ.(1999). Induction of ARF tumor suppressor geneexpression and cell cycle arrest by transcription factor DMP1. Proc Natl Acad SciUSA96:3993–3998.
[18] Inoue K, WenR,Rehg JE,Adachi M, Cleveland JL, RousselMF et al.(2000).Disruption of the ARF transcriptional activator DMP1facilitates cell immortalization,Ras transformation, and tumorigenesis. Genes Dev14:1797–1809.
[19] McMahon M, Woods D.(2001). Regulation of the p53pathway by Ras, the plotthickens. Biochem Biophys Acta1471:M63–M71.
[20] Inoue K, Zindy F, Randle DH, Rehg JE, Sherr CJ.(2001). Dmp1is haplo-insufficientfor tumor suppression and modifies the frequencies of Arf and p53mutations inMycinduced lymphomas. Genes Dev15:2934–2939.
[21] Eischen CM, Weber JD, Roussel MF, Sherr CJ, Cleveland JL.(1999). Disruption ofthe ARF-Mdm2-p53tumor suppressor pathway in Myc-induced lymphomagenesis.Genes Dev13:2658–2669.
[22] Brooksbank C.(2001). Tumor suppressors. One-hit wonders? Nature Rev Cancer1:174.
[23] Sreeramaneni R, Chaudhry A, McMahon M, Sherr CJ, Inoue K.(2005). Ras-Raf-Arfsignaling critically depends on Dmp1transcription factor. Mol Cell Biol25:220–232.
[24] Palmero I, Murga M, Zubiaga A, Serrano M.(2002). Activation of ARF by oncogenicstress in mouse fibroblasts is independent of E2F1and E2F2. Oncogene21:2939–2947.
[25] Rowland BD, Denissov SG, Douma S, Stunnenberg HG, Bernards R, Peeper DS.(2002). E2F transcriptional repressor complexes are critical downstream targets ofp19(ARF)/p53-induced proliferative arrest. Cancer Cell2:55–65.
[26] Aslanian, A., Iaquinta, P.J., Verona, R. and Lees, J.A.2004. Repression of the Arftumor suppressor by E2F3is required for normal cell cycle kinetics. Genes Dev.,18:1413–22.
[27] Taneja, P., Frazier, D.P., Sugiyama, T., Lagedrost, S. and Inoue, K.2007. Control ofcellular physiology by transcription factors E2F and their roles in carcinogenesis.Research Signpost (Review), in press.
[28] Mallakin, A., Taneja, P., Matise, L.A., Willingham, M.C. and Inoue, K.2006.Expression of Dmp1in specifi c differentiated, nonproliferating cells and
[29] Mallakin A, Taneja P, Matise LA, Willingham MC, Inoue K.(2006). Expression ofDmp1in specific differentiated,nonproliferating cells and its repression by E2Fs.Oncogene25:7703–7713.
[30] Aslanian A, Iaquinta PJ, Verona R, Lees JA.(2004). Repression of the Arf tumorsuppressor by E2F3is required for normal cell cycle kinetics. Genes Dev18:1413–1422.
[31] Crowe DL, Nguyen DC, Tsang KJ, Kyo S.(2001). E2F-1represses transcription ofthe human telomerase transcriptase gene. Nucl Acid Res29:2789–2794.
[32] Lu Z, Luo RZ, Peng H, Huang M, Nishimoto A, Hunt KK et al.(2006). E2F-HDACcomplexes negatively regulate the tumor suppressor gene ARHI in breast cancer.Oncogene25:230–239.
[33] its repression by E2Fs. Oncogene,25:7703–13. Perkins, N.D.2004. NF-κB: tumorpromoter or suppressor? Trends Cell. Biol.,14:64–9.
[34] Hayden M.S. and Ghosh, S.2004. Signaling to NF-κB. Genes Dev.,18:2195–224.
[35] Sherr, C.J.2004. Principles of tumor suppression. Cell.,116:235–46.
[36] Ruas, M. and Peters, G.1998. The p16INK4a/CDKN2A tumor suppressor and itsrelatives. Biochim. Biophys. Acta. Rev. Cancer,1378: F115–77.
[37] Inoue K., Mallakin, A. and Frazier, D.P.2007.Dmp1and tumor suppression.Oncogene,26:4329–35.
[38] Trovato M, Ulivieri A, Dominici R, Ruggeri RM, Vitarelli E, Benvenga S et al.(2004).Clinico-pathological significance ofcell-type-specific loss of heterozygosity onchromosome7q21:analysis of318microdissected thyroid lesions. EndocrRelat Cancer11:365–376.
[39] Tschan MP, Fischer KM, Fung VS, Pirnia F, Borner MM, Fey MF et al.(2003).Alternative splicing of the human cyclin D-binding Myb-like protein (hDMP1) yieldsa truncated protein isoform that alters macrophage differentiationpatterns. J BiolChem278:42750–42760.
[40] Kiriakidou M, Nelson PT, Kouranov A, Fitziev P, Bouyioukos C, Mourelatos Z et al.(2004). A combined computational experimental approach predicts human microRNAtargets. Genes Dev18:1165–1178.
[41] Elmaagacli AH, Koldehoff M, Peceny R, et al.(2005). WT1and BCR-ABL specificsmall interfering RNA have additive effects in the induction of apoptosis in leukemiccells. Leukemogenesis90:326–334.
[42] Cimmino A, Calin GA, Fabbri M, et al.(2005). miR-15and miR-16induce apoptosisby targeting BCL2. Proc Natl Acad Sci USA102:13944–13949.
[43] Calin GA, Croce CM.(2006). Genomics of chronic lymphocytic leukemiamicroRNAs as new players with clinical significance. Semin Oncol33:167–173.
[44] Sugiyama T, Frazier DP, Taneja P, et al. Signal transduction involving the dmp1transcription factor and its alteration in human cancer. Clinical medicine Oncology2008,2:209-219.
[2] Sugiyama T, Frazier DP, Taneja P, et al. Signal transduction involving the dmp1transcription factor and its alteration in human cancer. Clin Med Oncol.2008;2:209-219.
[3] Hou HA, Huang TC, Lin LI, et al. WT1mutation in470adult patients with acutemyeloid leukemia: stability during disease evolution and implication of itsincorporation into a survival scoring system. Blood.2010;115:5222-5231.
[4]顾伟英,陈子兴,胡绍燕,等. WT1基因水平动态检测对白血病患者异基因骨髓移植后微小残留病监测的意义.中华医学杂志.2005;85:444-447.
[5]顾伟英,曹祥山,邱国强,等. WT1基因肽诱导细胞毒性T淋巴细胞免疫治疗白血病的实验研究.中华医学杂志.2005;85:3475-3480.
[6]顾伟英,陈子兴,邱国强,等.肾母细胞瘤基因衍生肽诱导细胞毒性t淋巴细胞对白血病患者骨髓CD34+细胞的体外杀伤效应.中华医学杂志.2008;88:3401-3406.
[7] Algar E. A review of the Wilms' tumor1gene (WT1) and its role in hematopoiesisand leukemia. J Hematother Stem Cell Res.2002;11:589-599.
[8] Tschan MP, Gullberg U, Shan D, et al. The hDMP1tumor suppressor is a new WT1target in myeloid leukemias. Leukemia.2008;22:1087-1090.
[9]江庭秀,顾伟英,邱国强,等.辛伐他汀联合全反式维甲酸对人早幼粒细胞白血病细胞株WT1/hDMP1基因表达的影响.中华医学杂志.2011;91:1856-1860.
[10] Elmaagacli AH, Koldehoff M, Peceny R, et al. WT1and BCR-ABL specific smallinterfering RNA have additive effects in the induction of apoptosis in leukemiccells. Haematologica.2005;90:326-334.
[11] Rizzi M, Tschan MP, Britschgi C, et al. The death-associated protein kinase2isup-regulated during normal myeloid differentiation and enhances neutrophilmaturation in myeloid leukemic cells. J Leukoc Biol.2007;81:1599-1608.
[12] Svedberg H, Chylicki K, Baldetorp B, et al. Constitutive expression of the Wilms'tumor gene (WT1) in the leukemic cell line U937blocks parts of the differentiationprogram. Oncogene.1998;16:925-932.
[13] Falini B, Mecucci C, Tiacci E, et al. Cytoplasmic nucleophosmin in acutemyelogenous leukemia with a normal karyotype. N Engl J Med.2005;352:254-266.
[14] Yan LZ, Chen SN, Liang JY, et al.[Analysis of NPM1gene mutations in acutemyeloid leukemia]. Zhonghua Xue Ye Xue Za Zhi.2007;28:289-293.
[15] Cloos J, Goemans BF, Hess CJ, et al. Stability and prognostic influence of FLT3mutations in paired initial and relapsed AML samples. Leukemia.2006;20:1217-1220.
[16] Gu W, Chen Z, Hu S, et al. Changes in expression of WT1isoforms during induceddifferentiation of the NB4cell line. Haematologica.2005;90:403-405.
[1]江庭秀,顾伟英,邱国强等.辛伐他汀联合全反式维甲酸对人早幼粒细胞白血病细胞株WT1/hDMP1基因表达的影响.中华医学杂志.2011;91:1856-1860..
[2]顾伟英,陈子兴,胡绍燕等.WT1基因水平动态检测对白血病患者异基因骨髓移植后微小残留病监测的意义.中华医学杂志.2005;85:444-447..
[3] Quentmeier H，Martelli MP，Dirks WG，et a1．Cell line OCI／AML3bearsexon-12NPM gene mutation-A and cytoplasmic expression ofnucleophosmin．Leukemia，2005，19：1760—1767．
[4]王莉红，周春林，张新伟等. FLT3基因内部串联重复突变与急性白血病的关系及临床意义.中华血液学杂志,2004,25:393-396.
[5] Grimwade D, Walker H, Harrison G, et al. The predictive value of hierarchicalcytogenetic classification in older adults with acute myeloid leukemia (AML):analysis of1065patients entered into the United Kingdom Medical ResearchCouncil AML11trial. Blood.2001;98:1312-1320.
[6] Sugiyama T, Frazier DP, Taneja P, et al. Signal transduction involving the dmp1transcription factor and its alteration in human cancer. Clin Med Oncol.2008;2:209-219.
[7] Tschan MP, Gullberg U, Shan D, et al. The hDMP1tumor suppressor is a new WT1target in myeloid leukemias. Leukemia.2008;22:1087-1090.
[8] Tschan MP, Fischer KM, Fung VS, et al. Alternative splicing of the human cyclinD-binding Myb-like protein (hDMP1) yields a truncated protein isoform that altersmacrophage differentiation patterns. J Biol Chem.2003;278:42750-42760.
[9] Elmaagacli AH, Koldehoff M, Peceny R, et al. WT1and BCR-ABL specific smallinterfering RNA have additive effects in the induction of apoptosis in leukemiccells. Haematologica.2005;90:326-334.
[10] Inoue K, Mallakin A, Frazier DP. Dmp1and tumor suppression. Oncogene.2007;26:4329-4335.
[11] Santamaria CM, Chillon MC, Garcia-Sanz R, et al. Molecular stratification modelfor prognosis in cytogenetically normal acute myeloid leukemia. Blood.2009;114:148-152.
[12] Ho PA, Zeng R, Alonzo TA, et al. Prevalence and prognostic implications of WT1mutations in pediatric acute myeloid leukemia (AML): a report from the Children'sOncology Group. Blood.2010;116:702-710.
[13] Suzuki T, Kiyoi H, Ozeki K, et al. Clinical characteristics and prognosticimplications of NPM1mutations in acute myeloid leukemia. Blood.2005;106:2854-2861.
[14] Falini B, Mecucci C, Tiacci E, et al. Cytoplasmic nucleophosmin in acutemyelogenous leukemia with a normal karyotype. N Engl J Med.2005;352:254-266.
[15] Thiede C, Koch S, Creutzig E, et al. Prevalence and prognostic impact of NPM1mutations in1485adult patients with acute myeloid leukemia (AML). Blood.2006;107:4011-4020.
[16] Chen W, Rassidakis GZ, Li J, et al. High frequency of NPM1gene mutations in acutemyeloid leukemia with prominent nuclear invaginations ("cuplike" nuclei). Blood.2006;108:1783-1784.
[17] Schneider F, Hoster E, Schneider S, et al. Age-dependent frequencies of NPM1mutations and FLT3-ITD in patients with normal karyotype AML (NK-AML). AnnHematol.2012;91:9-18.
[18] Kim HJ. Mutations in AML with a normal karyotype: NPM1and FLT3-ITD, ready touse as a key prognosticator? Korean J Hematol.2010;45:79-80.
[19] Hou HA, Huang TC, Lin LI, et al. WT1mutation in470adult patients with acutemyeloid leukemia: stability during disease evolution and implication of itsincorporation into a survival scoring system. Blood.2010;115:5222-5231.
[20]顾伟英,曹祥山,邱国强等. WT1基因肽诱导细胞毒性T淋巴细胞免疫治疗白血病的实验研究.中华医学杂志.2005;85:3475-3480.
[21]顾伟英,陈子兴,邱国强等.肾母细胞瘤基因衍生肽诱导细胞毒性T淋巴细胞对白血病患者骨髓CD34+细胞的体外杀伤效应.中华医学杂志.2008;88:3401-3406.
[1] Sherr CJ.(2000). The Pezcoller lecture: cancer cell cycle revisited. Cancer Res60:3689–3695.
[2] Sherr CJ, Robers JM.(2004). Living with or without cyclin and cyclin-dependentkinases. Genes Dev18:2699–2711.
[3] Giacinti C, Giordano A.(2006).RB and cell cycle progression. Oncogene25:5220–5227.
[4] Evers R, Grummt I.(1995). Molecular coevolution of mammalian ribosomal geneterminator sequences and the transcription termination factor TTF-1. Proc Natl AcadSci USA92:5827–5831.
[5] Inoue K, Sherr CJ.(1998). Gene expression and cell cycle arrest mediated bytranscription factor DMP1is antagonized by D-type cyclins through acyclin-dependent-kinase independent mechanism. Mol Cell Biol18:1590–1600.
[6] Hirai H, Sherr CJ.(1996). Interaction of D-type cyclins with a novel myb-liketranscription factor, DMP1. Mol Cell Biol16:6457–6467.
[7] Cheng M, Sexl V, Sherr CJ, Roussel MF.(1998). Assembly of cyclin D-dependentkinase and titration of p27kip1regulated by mitogen-activated protein kinase kinase(MEK1). Proc Natl Acad Sci USA95:1091–1096.
[8] Oh I-H, Reddy EP.(1999). The myb gene family in cell growth, differentiation, andapoptosis. Oncogene18:3017–3033.
[9] Bernards R.(1999). CDK-independent activities of D type cyclins. Biochem BiophysActa1424(2–3):M17–M22.
[10] Zwijsen R, Wientjens E, Klompmaker R, van der Sman J, Bernards R, Michalides R.(1997). CDK-independent activation of estrogen receptor by cyclin D1. Cell88:405–415.
[11] Adnane, J., Shao, Z. and Robbins, P.D.1999. Cyclin D1associates with theTBP-associated factor TAF(II)250to regulate Sp1-mediated transcription.Oncogene,18:239–47.
[12] Reutens, A.T., Fu, M., Wang, C., Albanese, C., McPhaul, M.J., Sun, Z., Balk, S.P.,Janne, O.A., Palvimo, J.J. and Pestell, R.G.2001. Cyclin D1binds the androgenreceptor and regulates hormone-dependent signaling in a p300/CBP-associated factor(P/CAF)-dependent manner. Mol. Endocrinol.,15:797–811.
[13] Ganter B, Fu S, Lipsick JS.(1998). D-type cyclins repress transcriptional activationby the v-Myb but not the c-Myb DNA-binding domain. EMBO J17:255–268.
[14] Horstmann S, Ferrari S, Klempnauer KH.(2000). Regulation of B-Myb activity bycyclin D1. Oncogene19:298–306.
[15] Landis MW, Pawlyk BS, Li T, Sicinski P, Hinds PW.(2006). Cyclin D1-dependentkinase activity in murine development and mammary tumorigenesis. Cancer Cell9:13–22.
[16] Kim WY, Sharpless NE.(2006). The regulation of INK4/ARF in cancer and aging.Cell127:265–275.
[17] Inoue K, Roussel MF, Sherr CJ.(1999). Induction of ARF tumor suppressor geneexpression and cell cycle arrest by transcription factor DMP1. Proc Natl Acad SciUSA96:3993–3998.
[18] Inoue K, WenR,Rehg JE,Adachi M, Cleveland JL, RousselMF et al.(2000).Disruption of the ARF transcriptional activator DMP1facilitates cell immortalization,Ras transformation, and tumorigenesis. Genes Dev14:1797–1809.
[19] McMahon M, Woods D.(2001). Regulation of the p53pathway by Ras, the plotthickens. Biochem Biophys Acta1471:M63–M71.
[20] Inoue K, Zindy F, Randle DH, Rehg JE, Sherr CJ.(2001). Dmp1is haplo-insufficientfor tumor suppression and modifies the frequencies of Arf and p53mutations inMycinduced lymphomas. Genes Dev15:2934–2939.
[21] Eischen CM, Weber JD, Roussel MF, Sherr CJ, Cleveland JL.(1999). Disruption ofthe ARF-Mdm2-p53tumor suppressor pathway in Myc-induced lymphomagenesis.Genes Dev13:2658–2669.
[22] Brooksbank C.(2001). Tumor suppressors. One-hit wonders? Nature Rev Cancer1:174.
[23] Sreeramaneni R, Chaudhry A, McMahon M, Sherr CJ, Inoue K.(2005). Ras-Raf-Arfsignaling critically depends on Dmp1transcription factor. Mol Cell Biol25:220–232.
[24] Palmero I, Murga M, Zubiaga A, Serrano M.(2002). Activation of ARF by oncogenicstress in mouse fibroblasts is independent of E2F1and E2F2. Oncogene21:2939–2947.
[25] Rowland BD, Denissov SG, Douma S, Stunnenberg HG, Bernards R, Peeper DS.(2002). E2F transcriptional repressor complexes are critical downstream targets ofp19(ARF)/p53-induced proliferative arrest. Cancer Cell2:55–65.
[26] Aslanian, A., Iaquinta, P.J., Verona, R. and Lees, J.A.2004. Repression of the Arftumor suppressor by E2F3is required for normal cell cycle kinetics. Genes Dev.,18:1413–22.
[27] Taneja, P., Frazier, D.P., Sugiyama, T., Lagedrost, S. and Inoue, K.2007. Control ofcellular physiology by transcription factors E2F and their roles in carcinogenesis.Research Signpost (Review), in press.
[28] Mallakin, A., Taneja, P., Matise, L.A., Willingham, M.C. and Inoue, K.2006.Expression of Dmp1in specifi c differentiated, nonproliferating cells and
[29] Mallakin A, Taneja P, Matise LA, Willingham MC, Inoue K.(2006). Expression ofDmp1in specific differentiated,nonproliferating cells and its repression by E2Fs.Oncogene25:7703–7713.
[30] Aslanian A, Iaquinta PJ, Verona R, Lees JA.(2004). Repression of the Arf tumorsuppressor by E2F3is required for normal cell cycle kinetics. Genes Dev18:1413–1422.
[31] Crowe DL, Nguyen DC, Tsang KJ, Kyo S.(2001). E2F-1represses transcription ofthe human telomerase transcriptase gene. Nucl Acid Res29:2789–2794.
[32] Lu Z, Luo RZ, Peng H, Huang M, Nishimoto A, Hunt KK et al.(2006). E2F-HDACcomplexes negatively regulate the tumor suppressor gene ARHI in breast cancer.Oncogene25:230–239.
[33] its repression by E2Fs. Oncogene,25:7703–13. Perkins, N.D.2004. NF-κB: tumorpromoter or suppressor? Trends Cell. Biol.,14:64–9.
[34] Hayden M.S. and Ghosh, S.2004. Signaling to NF-κB. Genes Dev.,18:2195–224.
[35] Sherr, C.J.2004. Principles of tumor suppression. Cell.,116:235–46.
[36] Ruas, M. and Peters, G.1998. The p16INK4a/CDKN2A tumor suppressor and itsrelatives. Biochim. Biophys. Acta. Rev. Cancer,1378: F115–77.
[37] Inoue K., Mallakin, A. and Frazier, D.P.2007.Dmp1and tumor suppression.Oncogene,26:4329–35.
[38] Trovato M, Ulivieri A, Dominici R, Ruggeri RM, Vitarelli E, Benvenga S et al.(2004).Clinico-pathological significance ofcell-type-specific loss of heterozygosity onchromosome7q21:analysis of318microdissected thyroid lesions. EndocrRelat Cancer11:365–376.
[39] Tschan MP, Fischer KM, Fung VS, Pirnia F, Borner MM, Fey MF et al.(2003).Alternative splicing of the human cyclin D-binding Myb-like protein (hDMP1) yieldsa truncated protein isoform that alters macrophage differentiationpatterns. J BiolChem278:42750–42760.
[40] Kiriakidou M, Nelson PT, Kouranov A, Fitziev P, Bouyioukos C, Mourelatos Z et al.(2004). A combined computational experimental approach predicts human microRNAtargets. Genes Dev18:1165–1178.
[41] Elmaagacli AH, Koldehoff M, Peceny R, et al.(2005). WT1and BCR-ABL specificsmall interfering RNA have additive effects in the induction of apoptosis in leukemiccells. Leukemogenesis90:326–334.
[42] Cimmino A, Calin GA, Fabbri M, et al.(2005). miR-15and miR-16induce apoptosisby targeting BCL2. Proc Natl Acad Sci USA102:13944–13949.
[43] Calin GA, Croce CM.(2006). Genomics of chronic lymphocytic leukemiamicroRNAs as new players with clinical significance. Semin Oncol33:167–173.
[44] Sugiyama T, Frazier DP, Taneja P, et al. Signal transduction involving the dmp1transcription factor and its alteration in human cancer. Clinical medicine Oncology2008,2:209-219.